Local tolerance

Traditionally, global tolerances have been specified for any point on the floor relative to datum and local tolerances specified relative to a 3 m straight edge. For VNA type requirements tolerances distinguish between areas of defined movement (i.e. predetermined vehicle routes) and areas of free movement (the rest of the slab). 

Oral or parenteral Several days (up to 3) Up to 2 weeks I, II, III, NDA I II III, NDA 2 species 2 weeks 2 species 4 weeks 2 species up to 4 weeks 2 species up to 3 months For parenterally administered drugs compatibility with blood and local tolerance at injection site where applicable. 

Both irritation and local tolerance studies assess the short-term hazard of pharmaceutical agents in the immediate region of their application or installation. In particular, these studies are done (expected) to assess topically or parenterally administered drugs. 

For the skin, this scale is used in the primary dermal irritation test, which is performed for those agents that are to be administered to patients by application to the skin. As with all local tolerance tests, it is essential that the material be evaluated in condition of use, that is, in the final formulated form, applied to test animals in the same manner that the agent is to be used clinically. 

Part III This part is to ensure that safety tests have been carried out according to GLPThe data to be submitted are toxicity (single dose and repeated dose), reproduction function, embryo-fetal and perinatal toxicity, mutagenic potential, carcinogenic potential, pharmacodynamics, pharmacokinetics, and local tolerance. 

Part III H Local Tolerance Part III Q Other Information... 

Recent guidelines entitled Non-clinical Local Tolerance Testing of Medicinal Product from the CPMP refer to the murine local l)unph node assay as a method for the assessment of the induction phase of skin sensitisation. This method measures the ability of compoimds to induce proliferative responses in skin-draining lymph nodes. This method uses fewer animals than alternative in vivo methods and reduces the trauma to which animals are potentially subjected. ... 

EMEA Note for Guidance on non-chnical local tolerance testing of human pharmaceuticals, http //www.emea. europa.eu/pdfs/human/swp/214500en. 

It is only infrequently that local tolerance of a compound can have effects on the reproductive outcome. For most topically applied compounds, the degree of absorption and systemic exposure is likely to be low for the adult and hence for the conceptus. If severe local effects are induced such that the integrity of the skin is compromised and its barrier function reduced, then it is possible for larger amounts to be absorbed systemically and reproductive effects might be more likely. The local tolerance in clinical use and the human systemic exposure should be considered in determining whether any effects in animals are likely to be clinically relevant. 

Dhondt, M.M.M., et al. 2005. The evaluation of the local tolerance of vaginal formulations containing dapivirine using the slug mucosal irritation test and the rabbit vaginal irritation test. Eur J Pharm Biopharm 60 419. 

For some of the effects the concentration in the products is most important, for example, the local tolerance on the skin and eye. For some of the other effects it is necessary to estimate the presumed use by a normal or perhaps an eager user and the total amounts are more adequate. Guidance to relevant exposure estimation can be found in part 6 of SCCNFP. Safety evaluation of finished products in the notes of guidance.3 The European cosmetics industry has, for example, estimated the exposure levels to be 0.8 g/day of face cream, 1-2 g/day of general cream and 8-16 g/day of body lotion for a female user.10 It is also important to predict the use of the special product and the expectations from the single user. Groups of users with especially sensitive skin are important to take into account. 

Adequate evaluation of patient acceptability and compliance of buccal patches should include a clinical examination to observe local tolerance, and the incidence and degree of irritation. Trials should also involve the use of questionnaires, in order to determine a subject assessment of such factors as ... 

Local tolerance assessments are usually incorporated into repeat-dose toxicity studies. Specific assessments include clinical observations (e.g.,Draize scoring) and macroscopic and microscopic evaluations of the injection site. These types of studies may also be used to test formulation changes during the course of clinical development. 

Assess local tolerance (infusion toxicity, implant site reaction, local microenvironment, release of paracrine factors). 

As a result of these unique delivery routes, there is an increased potential for toxicity to tissues at or near the injection site. Assessment of local tolerance and tissue compatibility of the clinical formulation is usually evaluated as part of the animal model of efficacy and/or general toxicity study, thus obviating the need for separate local tolerance studies. There may be additional concerns in cases where analogous products are used including potential differences in formulation, stability, and so forth. 

Irritation Sensitization Acute systemic toxicity Subchronic toxicity Local tolerance... 

Study for Effects on Pre- and Postnatal Development, Including Maternal Function in the Monkey (Segment 3) Local Tolerance ICH S5 A Detection of Toxicity to Reproduction for Medicinal Products 39-52 21-34 1,000,000-1,500,00 ... 

Other mitogenicity in CHO-K1 and human BIO osteosarcoma cells, human hepatoma cells and MCF-7 cells to include drug binding study to IGF-1 and insulin receptors local tolerance in pigs immunogenicity studies in rabbits... 

For brevity, only the pivotal toxicology studies are given. Examples of studies not included are proof-of-concept, comparability, toxicokinetic, pharmacokinetic, pharmacodynamic, local tolerance, and miscellaneous in vitro and in vivo studies. Pharmacokinetic and pharmacodynamic experiments generally used the pivotal toxicology animal model(s) because of the species specificity of the biopharmaceutical. 

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